Comparison of Gene Expression Responses in the Small Intestine of Mice Following Exposure to 3 Carcinogens Using the...

Area of Science:

• Toxicology
• Molecular Biology
• Carcinogenesis

Background:

• Small intestine carcinogenesis is rare in humans and rodents.
• Hexavalent chromium (Cr(VI)), captan, and folpet are known to induce intestinal carcinogenesis in mice.
• Previous studies showed similar histopathological responses in mice exposed to these agents.

Purpose of the Study:

• To analyze the transcriptomic responses to Cr(VI), captan, and folpet exposure in mouse duodenum.
• To identify common molecular mechanisms underlying intestinal carcinogenesis induced by these agents.
• To inform the development of an adverse outcome pathway for intestinal cancer.

Main Methods:

• TempO-Seq technology was used to analyze transcriptomic responses.
• Formalin-fixed, paraffin-embedded duodenal sections from mice exposed to Cr(VI), captan, or folpet were analyzed.
• Gene expression data was compared to identify differentially expressed genes and pathways.

Main Results:

• Transcriptional responses were similar across all three agents.
• 126/546 (23%) differentially expressed genes were altered in the same direction.
• 25 pathways were upregulated, including those related to cellular metabolism, stress, inflammation, cell proliferation, hypoxia-inducible factor 1 (HIF-1), and activator protein 1 (AP1) signaling.

Conclusions:

• Cr(VI), captan, and folpet induce similar molecular, cellular, and tissue-level changes in the mouse duodenum.
• The identified molecular changes are linked to intestinal injury, angiogenesis, and carcinogenesis.
• These findings support the development of a shared adverse outcome pathway for intestinal cancer.